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Anticancer Drugs. 2019 Sep 3. doi: 10.1097/CAD.0000000000000825. [Epub ahead of print]

Ibuprofen induces ferroptosis of glioblastoma cells via downregulation of nuclear factor erythroid 2-related factor 2 signaling pathway.

Gao X1,2, Guo N2, Xu H1,2, Pan T3, Lei H2, Yan A2, Mi Y2, Xu L1,2.

Author information

1
Department of Anesthesiology, School of Stomatology, State Key Laboratory of Military Stomatology, The Fourth Military Medical University.
2
Shaanxi Key Laboratory of Brain Disorders and Institute of Basic Medical Sciences.
3
School of Public Health, Xi'an Medical University, Xi'an, China.

Abstract

Ferroptosis is a newly discovered type of cell death decided by iron-dependent lipid peroxidation, but its role in glioblastoma cell death remains unclear. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has been associated with antitumorigenic effects in many cancers. In this study, we first found that ibuprofen inhibited the viabilities of glioblastoma cells in vitro and in vivo, accompanied by abnormal increase in intracellular lipid peroxidation. Further study showed that the cell growth inhibition caused by ibuprofen could be rescued by the ferroptosis inhibitors deferoxamine (DFO), ferrostatin-1 and Liproxstatin-1. Nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) are key regulators of ferroptosis. Our data showed that Nrf2, GPX4 and SLC7A11 were downregulated in glioblastoma cells under ibuprofen treatment. Interestingly, we found that decreased mRNA expression of GPX4 and SLC7A11 was accompanied with reduced Nrf2, which is a redox sensitive transcription factor that controls the expression of intracellular redox-balancing proteins such as GPX4 and SLC7A11. All the data suggested that Nrf2 could regulate the expression of GPX4 and SLC7A11 in glioma cells. Taken together, our findings reveal that ibuprofen could induce ferroptosis of glioblastoma cells via downregulation of Nrf2 signaling pathway and is a potential drug for glioma treatment.

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